In the human brain more than 20 billion neurons become precisely connected to one another during development. How this happens, despite significant advances, remains for the most part, a mystery. Recently, we have found that the cell adhesion molecule L1 can bind directly to ezrin, radixin and moesin, members of the ERM family of molecules that link transmembrane proteins to the actin cytoskeleton. Work from other laboratories has established the importance of L1 in axon fasciculation and guidance, and our preliminary studies indicate that the ERM family plays a critical role in translating L1 binding into outgrowth. Work in non-neuronal cells suggests that ERMs act both upstream and downstream of the Rho family of small GTPases and that ERM binding to the tuberous sclerosis1 gene product, hamartin, is required for Rho mediated regulation of adhesion. This suggests that ERMs may be key regulators of actin dynamics during neural differentiation and pathfinding. The goal of the proposed work is to define the nature of ERM function in neurons, to address how ERMs are dynamically regulated in response to particular phases of neurite outgrowth and to changes in substrate, and to investigate the signaling pathways involved. The initial studies will be carried out in culture where environment can be closely controlled. Results from this work will inform the analysis and interpretation of an in vivo study of ERM function in the regulation of axon outgrowth and branching. [unreadable] [unreadable] [unreadable]